Polyhydroxyalkylpyrazine derivatives, their preparation and medicaments comprising them

ABSTRACT

The present invention relates to compounds of formula (I)  
                 
 
     in which  
     R 1  is any of the stereoisomeric forms of the chain 
     —(CHOH) 3 —CH 2 OH  (II) 
     and either (A) R 2  is a hydrogen atom and R 3  is any of the stereoisomeric forms of the chain 
     —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
     or (B) R 2  is any of the stereoisomeric forms of the chains 
     —(CHOH) 3 —CH 2 OH  (II) 
     and 
     —CH 2 —(CHOH) 2 —CH 2 OH  (III) 
     and R 3  is a hydrogen atom, or their salts with an inorganic or organic acid, in a pharmaceutically acceptable vehicle, provided, however, that said compound is not  
     fructosazine of formula  
                 
 
     deoxyfructosazine of formula  
                 
 
     a compound of formula  
                 
 
     and to methods of making such compounds, as well as to a method for the treatment or prevention of diabetes or complications of diabetes, this method comprising administering to a patient in need of such treatment an effective amount of a compound of formula (I).

[0001] The present invention relates to medicaments comprising, asactive principle, at least one compound of general formula: in theirstereoisomeric forms or their salts with an inorganic or organic acid,to novel compounds of formula (I) or their salts with an inorganic ororganic acid, and to their preparation.

[0002] In the general formula (I): R₁ represents the stereoisomericforms of the chain

—(CHOH)₃—CH₂OH  (II)

[0003] and either R₂ represents a hydrogen atom and R₃ represents thestereoisomeric forms of the chain

—CH₂—(CHOH)₂—CH₂OH  (III)

[0004] or R₂ represents the stereoisomeric forms of the chains

—(CHOH)₃—CH₂OH  (II)

[0005] or

—CH₂—(CHOH)₂—CH₂OH  (III)

[0006] and R₃ represents a hydrogen atom with the exception of

[0007] fructosazine of formula

[0008] deoxyfructosazine of formula

[0009] and the compound of formula

[0010] The medicaments according to the invention thus comprise at leastone stereoisomer of the following compounds: or a salt of such acompound with an organic or inorganic acid, with the exception offructosazine, deoxyfructosazine and the compound of formula (VI).

[0011] The medicaments according to the invention are preferably thosewhich comprise, as active principle, at least one compound of formula(I) chosen from the following compounds:

[0012]1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0013]1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0014]1-[5-(1R,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0015]1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0016]1-[5-(1S,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0017]1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0018]1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0019]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0020]1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0021]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0022]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0023]1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0024]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0025]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0026]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0027]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0028]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0029]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0030]1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0031]1-[6-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0032] or a salt of such a compound with an inorganic or organic acid,and, more advantageously still, those which comprise, as activeprinciple, at least one compound of formula (I) chosen from thefollowing compounds:

[0033]1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0034]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0035]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0036]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0037]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0038] or a salt of such a compound with an inorganic or organic acid.

[0039] The following compounds are known:

[0040] fructosazine, deoxyfructozasine and the compound of formula (VI)are described (Patent JP 43-13469, Ann., 644, 122-127 (1961); Agr. Biol.Chem., 39 (5), 1143-1148 (1975)),

[0041] the stereoisomers of general formula (VIa), (VIb), (VIc) and(VId) mentioned hereinbelow have been described (Patent JP 43-13469,Carbohyd. Res., 26(2), 377-84 (1973), J. Anal. Appl. Pyrolysis, 13,191-198(1988))

[0042] the compounds of general formulae (VII), (VIII) and (IX)resulting from glucose, fructose, mannose and galactose have beendescribed in Japanese Patent JP 53-90401.

[0043] However, their use as medicament has not been mentioned and thisis the subject-matter of the present invention.

[0044] The compounds of formula (I) or their salts with an inorganic ororganic acid, with the exception of the following compounds: are noveland, as such, form part of the invention.

[0045] The preferred compounds of formula (I) are the following:

[0046]1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0047]1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0048]1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0049]1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0050]1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0051]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0052]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0053]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0054]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0055]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0056]1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0057] or a salt of such a compound with an inorganic or organic acid,advantageously

[0058]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0059]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0060]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0061] or a salt of such a compound with an inorganic or organic acid,and, more advantageously still, the following compound:

[0062]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0063] or a salt of such a compound with an inorganic or organic acid.

[0064] The stereoisomeric forms of the compounds of general formula (I)are obtained from the stereoisomeric forms of the reactants hereinbelowused by the preparation process according to the invention.

[0065] The stereoisomers of the compounds of formula (I) in which R₁represents the stereoisomeric forms of the —(CHOH) ₃—CH₂OH chain (II),R₂ represents a hydrogen atom and R₃ represents the stereoisomeric formsof the —CH₂—(CHOH)₂—CH₂OH chain (III), that is to say the compoundsrepresented by the general formula (VII), can be obtained by reaction ofammonium formate with an aldose, or a mixture of 2 aldoses, of thedextrorotatory or laevorotatory series, of general formula:

CHO—CHOH—R₁  (X)

[0066] in which R₁ has the same meaning as in the formula (I).

[0067] This reaction can preferably be carried out at a temperature ofbetween 15

C and 100

C, preferably in aqueous medium.

[0068] The aldoses are commercially available or can be obtained from:

[0069] a) commercially available aldoses:

[0070] by epimerization reactions, by application or adaptation of themethods described in Adv. Carbohydr. Chem., 13, 63, (1958), inparticular in basic medium by means of a dilute aqueous sodium hydroxidesolution (0.03 to 0.05%), at a temperature of between 20 and 40

C,

[0071] by chain-extension reactions, by application or adaptation of themethods described in “The Carbohydrates”, edited by W. Pigman and D.Horton, Academic Press, New York, Volume IA, 133 (1972), and inparticular by forming the cyanohydrin of the starting aldose (forexample, by reaction with sodium cyanide in aqueous solution, at atemperature of between 10 and 30

C and in the presence of sodium hydroxide, at a pH in the region of 9),then hydrolysis of the nitrile functional group thus formed to thecorresponding acid by application or adaptation of the methods describedin Organic Synthesis, Volume I, page 436 and Volume III, page 85 (forexample, using concentrated sulphuric acid or hydrochloric acid, inaqueous solution, at a temperature of between 20

C and the reflux temperature of the reaction mixture), and thenreduction of the carboxylic acid functional group to the correspondingaldehyde by application or adaptation of the methods described in J. Am.Chem. Soc., 71, 122 (1949), in particular using an alkali metalborohydride (for example, sodium borohydride), in aqueous solution, at atemperature of between 20

C and the boiling temperature of the reaction mixture,

[0072] by chain-shortening reactions, by application or adaptation ofthe methods described in “The Carbohydrates”, edited by W. Pigman and D.Horton, Academic Press, New York, Volume IB, 1980, page 929 or Chem.Ber., 83, 559 (1950) and in particular by converting the aldehydefunctional group of the aldose to the corresponding hydroxylamine byapplication or adaptation of the methods described in Organic Synthesis,Volume II, page 314 (for example, using hydroxylamine hydrochloride, inaqueous solution and in the presence of a base, such as sodiumcarbonate, at a temperature of between 20 and 50

C), and then reaction with 3,4-dinitrofluorobenzene in the presence ofcarbon dioxide and a base, such as sodium hydrogencarbonate, in aqueoussolution, and an aliphatic alcohol (for example, isopropyl alcohol), ata temperature of between 50 and 80

C,

[0073] b) corresponding allyl alcohols, by application or adaptation ofthe methods described in Science, 220, 949 (1983) and in particularusing tert-butyl hydroperoxide in the presence of a titanium(IV)complex, such as the titanium(IV) isopropoxide and optically puredialkyl tartrate (for example, diethyl tartrate) complex, followed bysuccessive reaction with sodium thiophenolate, para-chloroperbenzoicacid in acetic anhydride, and diisopropylaluminium hydride.

[0074] The stereoisomers of the sugar of formula (X) can be those ofaldoses containing 6 carbon atoms; those preferably used are D-gulose,D-galactose, D-allose, D-altrose, D-idose, D-talose, L-glucose,L-mannose, L-galactose, L-allose, L-altrose, L-idose, L-talose orL-gulose.

[0075] The stereoisomers of the compounds of formula (I) in which R₁represents the stereoisomeric forms of the —(CHOH)₃—CH₂OH chain (II), R₂represents the stereoisomeric forms of the —(CHOH)₃—CH₂OH chains (II)and R₃ represents a hydrogen atom, that is to say compounds representedby the general formula (VIII), can be obtained by treatment, in basicmedium, of an aminoaldose, or of a mixture of 2 aminoaldoses, of generalformula:

CHO—CH(NH₂)—R₁  (XI)

[0076] optionally in the form of an addition salt, such as thehydrochloride, in which R₁ has the same meaning as in the generalformula (I).

[0077] The reaction is preferably carried out at a temperature in theregion of 20

C and use is preferably made of an aqueous ammonia solution and moreparticularly a 28% solution.

[0078] The aminoaldoses of formula (XI) are commercially available orcan be prepared by application or adaptation of methods described in,for example:

[0079] (a) Methods Carbohydr. Chem., 7, 29 (1976), which consist inconverting the aldehyde functional group of the corresponding aldose toa nitroethylene group using nitromethane in basic medium (for example,sodium ethoxide) and in then successively treating the product obtainedwith a saturated aqueous ammonia solution, at a temperature of between20

C and 30

C, with Ba(OH) 2 in aqueous solution, at a temperature of between 20

C and 30

C, and finally [lacuna] dilute sulphuric acid (10 to 15%), at atemperature of between 20

C and 30

C,

[0080] (b) “The Amino Sugar”, edited by R. W. Jeanloz, Academic Press,New York, 1969, page 1 or “The Carbohydrates”, edited by W. Pigman andD. Horton, Academic Press, New York, Volume IB, 1980, page 664, whichconsist in converting the aldehyde functional group of the correspondingaldose to an imino group from a primary aromatic amine (for exampleaniline) and of subsequently successively reacting [lacuna] hydrocyanicacid, at a temperature of between 0

C and 20

C, and [lacuna] hydrogen in the presence of palladium, in a solvent suchas an ether (for example tetrahydrofuran) or an aliphatic alcohol (forexample, ethanol or methanol), at a temperature of between 20

C and 50

C.

[0081] The stereoisomers of the aminoaldose of formula (XI) can be thoseof aminoaldose comprising 6 carbon atoms; that preferably used isD-galactosamine, optionally in the form of an addition salt, such as thehydrochloride.

[0082] The stereoisomers of the compounds of formula (I) in which R₁represents the stereoisomeric forms of the —(CHOH)₃—CH₂OH chain (II), R₂represents the stereoisomeric forms of the —CH₂—(CHOH)₂—CH₂OH chains(III) and R₃ represents a hydrogen atom, that is to say compoundsrepresented by the general formula (IX), can be obtained either from anaminoaldose, or from a mixture of 2 aminoaldoses, of general formula:

CHO—CH(NH₂)—R₁  (XI)

[0083] in which R₁ has the same meaning as in the general formula (I),in acidic medium and more particularly in acetic acid medium andpreferably while carrying out the reaction at a temperature of between15

C and 100

C, or from a ketose, or from a mixture of 2 ketoses, of general formula:

HOCH₂CO—R₁  (XII)

[0084] in which R₁ has the same meaning as in the general formula (I),by reaction with ammonium formate and preferably while carrying out thereaction at a temperature of between 15

C and 100

C and preferably in aqueous medium.

[0085] The ketoses of formula (XII) are commercially available or can beprepared by application or adaptation of the methods described in, forexample: a) Adv. Carbohydr. Chem., 13, 63, (1958), which consist inreacting the corresponding aldose either with a base, such as calciumhydroxide, sodium hydroxide, pyridine or quinoline, or with an acid,such as sulphuric acid, in aqueous solution or in the pure phase, at atemperature of between 20 and 50

C, b) Tetrahedron Asymmetry, 7(8), 2185, (1996), J. Am. Chem. Soc.,118(33), 7653 (1996), J. Org. Chem., 60(13), 4294 (1995), TetrahedronLett., 33(36), 5157 (1992), J. Am. Chem. Soc., 113(17), 6678 (1991),Angew. Chem., 100(5), 737, (1988), J. Org. Chem., 57, 5899 (1992), whichconsist, for example, in condensing either hydroxypyruvaldehyde,1,3-dihydroxyacetone, 1,3-dihydroxyacetone monophosphate orhydroxypyruvic acid with a 2-hydroxyacetaldehyde which is substituted inthe 2 position and which is optionally optically pure, optionally in thepresence of an enzyme, such as a transketolase. This reaction isgenerally carried out in an aqueous solution, at a temperature ofbetween 20 and 50

C, optionally in the presence of a base (for example, sodium hydroxide),of barium chloride, of magnesium chloride or of zinc chloride.Derivatives possessing a 2-hydroxyacetaldehyde group are commerciallyavailable or can be prepared from aldoses by application or adaptationof the methods described in P. Collins and R. Ferrier, Monosaccharides,Their Chemistry and Their Roles in Natural Products, published by J.Wiley (1995), and M. Bols, Carbohydrate Building Blocks, published by J.Wiley (1996).

[0086] The stereoisomer of the aminoaldose of formula (XI) preferablyused is D-galactosamine.

[0087] The stereoisomers of the compounds of formula (XII) can be thoseof ketoses comprising 6 carbon atoms; those preferably used areD-psicose, D-sorbose, D-tagatose, L-psicose, L-fructose, L-sorbose orL-tagatose.

[0088] The reaction mixtures obtained by the various processes describedabove are treated according to conventional physical (evaporation,extraction, distillation, chromatography or crystallization, forexample) or chemical (formation of salts, for example) methods.

[0089] The compounds of formula (I) can optionally be converted toaddition salts with an inorganic or organic acid by the action of suchan acid in an organic solvent, such as an alcohol, a ketone, an ether ora chlorinated solvent. These salts also form part of the invention.

[0090] Mention may be made, as examples of pharmaceutically acceptablesalts, of the addition salts with inorganic or organic acids, such asacetate, propionate, succinate, benzoate, fumarate, maleate, oxalate,methanesulphonate, isethionate, theophyllinacetate, salicylate,methylenebis(b-oxynaphthoate), hydrochloride, sulphate, nitrate andphosphate.

[0091] The following examples more particularly illustrate thepreparation process used according to the invention.

EXAMPLE 1

[0092] A solution of 1.0 g of D-sorbose and 3.5 g of ammonium formate in4 cm³ of water is heated at reflux for 0.5 hour and then allowed to coolto room temperature. The mixture is concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 40

C. The brown residue is taken up successively in ethyl ether and tolueneand evaporated to dryness. The new residue is taken up in ethanol andfiltered. The filtrate is evaporated to give a brown oil. The operationis repeated several times until there is no longer any precipitate. Theresidue thus obtained is purified by chromatography on a silica(0.063-0.200 mm) column, elution being carried out with anethanol/n-butanol/28% aqueous ammonia solution/water 8/2/2/1 by volumemixture. The fractions containing the expected product are combined andconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 40

C. The sticky yellow solid obtained is taken up in a sufficient amountof ethanol/methanol to produce a solution, followed by the addition ofethyl ether until a precipitate begins to appear, which precipitate isfiltered. The product crystallizes to give 0.15 g of1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol inthe form of a beige solid which melts at 90

C.

[0093] [¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): 2.85 and2.93 (2 dd, respectively J=13 and 9 Hz and J=13 and 4 Hz, 2H, 5α CH₂),from 3.25 to 3.55 (mt, 6H, 2γ0 CH, 2δ CH₂, 5γ CH and 5δ CH₂), 3.76 (mt,1H, 2β CH), 3.91 (mt, 1H, 5β CH), from 4.35 to 4.65 (unresolved peak,6H, OH at 2β, OH at 2γ, OH at 2δ, OH at 5β, OH at 5γ and OH at 5δ), 4.78(t, J=4.5 Hz, 1H, 2α CH), 5.39 (d, J=4.5 Hz, 1H, OH at 2α), 8.43 (s, 1H,═CH at 6), 8.61 (s, 1H, ═CH at 3). α_(D) ²⁰=+71.3

1.3 (c=0.5%, MeOH)].

EXAMPLE 2

[0094] A suspension containing 1.0 g of D-galactosamine hydrochlorideand 0.73 cm³ of diethylamine is left stirring for 1 hour and thenfiltered. The filtrate is evaporated and dissolved in 10 cm³ of aqueousammonia solution comprising 28% of ammonia and left stirring at roomtemperature for three weeks. The mixture is then concentrated underreduced pressure (2.7 kPa) at a temperature in the region of 40

C to give a yellow oil which is taken up in methanol and filtered. Thefiltrate is evaporated to give an orange oil which is purified bychromatography on a silica (0.04-0.063 mm) column, elution being carriedout with an ethanol/n-butanol/28% aqueous ammonia solution/water 8/2/2/1by volume mixture. The fractions containing the expected product arecombined and concentrated under reduced pressure (2.7 kPa) at atemperature in the region of 40

C to give an orangey-yellow sticky solid. The latter is crystallizedfrom methanol and the solid is filtered to give 0.12 g of1-[5-(1R,2R,3R,4-tetrahydroxy-butyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraolin the form of a beige powder which melts at 109

C.

[0095] [¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): from 3.35to 3.50 (mt, 4H, 2δ CH₂O and 5δ CH₂O), from 3.70 to 3.85 (mt, 4H, 2β CH,2γ CH, 5β CH and 5γ CH), 4.24 (d, J=8 Hz, 2H, OH at 2β and OH at 5β),4.41 (d, J=6.5 Hz, 2H, OH at 2γ and OH at 5γ), 4.50 (broad t, J=6 Hz,2H, OH at 2δ and OH at 5δ), 4.64 (2 dd, J=7 and 6 Hz, 2H, 2α CH and 5αCH), 5.48 (d, J=6 Hz, 2H, OH at 2α and OH at 5α), 8.56 (s, 2H, ═CH at 3and ═CH at 6)].

EXAMPLE 3

[0096] A solution of 1.0 g of D-tagatose and 3.5 g of ammonium formatein 4 cm³ of water is heated at reflux for 0.5 hour and then allowed tocool to room temperature. The mixture is filtered and the residueconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 40

C to give a brown residue which is taken up successively in ethanol andethyl ether and evaporated to dryness. This residue is triturated inethyl ether and filtered. The brown solid is dissolved in ethanol.Sodium hydroxide is added to this solution to pH 12 and the solution isleft stirring for 40 hours; the formation of a precipitate is thenobserved. The reaction mixture is filtered and the filtrate isconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 40

C to give a yellow solid which is taken up in methanol/ethyl ether andfiltered. After evaporation of the filtrate, the residue is dissolved inmethanol and brought to pH 2 by addition of an ethanolic solution ofhydrochloric acid. The precipitate which is formed is filtered and thefiltrate is concentrated. The residue is purified by chromatography on asilica (0.040-0.063 mm) column, elution being carried out with anethanol/n-butanol/aqueous ammonia solution/water 8/2/1/1 by volumemixture. The fractions containing the expected product are combined andconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 40

C. The white solid thus obtained is recrystallized from methanol. 90 mgof 1-[5-(2R,3R,4-trihydroxybutyl)-pyrazin-2-yl]butane-1R,2R,3R,4-tetraolare obtained in the form of a white crystalline solid which melts at 146

C.

[0097] [¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): 2.86 (dd,J=14 and 9 Hz, 1H, 1H of the 5α CH₂), 2.92 (dd, J=14 and 3.5 Hz, 1H, theother H of the 5α CH₂), from 3.30 to 3.60 (mt, 5H, 2δ CH₂O, 5δ CH₂O and5γ CH), from 3.70 to 3.85 (mt, 2H, ²γ CH and 2β CH), 3.90 (mt, 1H, 5βCH), 4.22 (d, J=7 Hz, 1H, OH at 2β), 4.38 (d, J=6.5 Hz, 1H, OH at 2γ),4.43 (d, J=7 Hz, 1H, OH at 5β), from 4.40 to 4.55 (mt, 2H, OH at 2δ andOH at 5δ), from 4.55 to 4.70 (mt, 2H, 2α CH and OH at 5γ), 5.44 (d, J=6Hz, 1H, OH at 2α), 8.43 (s, 1H, ═CH at 6), 8.54 (s, 1H, ═CH at 3). α_(D)²⁰=−14.6

1.13 (c=0.2%, water)].

EXAMPLE 4

[0098] A solution of 10.0 g of L-sorbose and 7.0 g of ammonium formatein 28 cm³ of water is heated at reflux for 2.5 hours and then allowed tocool to room temperature. The mixture is concentrated under reducedpressure (2.7 kPa) at a temperature in the region of 50

C. The brown pasty residue is purified by chromatography on a silica(0.020-0.045 mm) column, elution being carried out with anethanol/n-butanol/aqueous ammonia solution/water 8/2/2/1 by volumemixture. The fractions containing the expected product are combined andconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 50

C. The brown oil obtained (9.1 g) is taken up in a mixture of 100 cm³ ofethanol and 10 cm³ of water. The mixture is brought to reflux, treatedwith 0.9 g of animal charcoal and then filtered on paper. The filtratedis concentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 50

C to give a brown oil (6.2 g). The latter is taken up in a mixture of 50cm³ of ethanol and 1.5 cm³ of water and recrystallized. The crystalsobtained are filtered, pulled dry and then washed with the same mixture.After drying to constant weight, 0.86 g of1-[5-(2S,3S,4-trihydroxybutyl)-pyrazin-2-yl]butane-1R,2S,3S,4-tetraol isobtained in the form of a beige crystalline solid melting at 116

C.

[0099]¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): 2.87 (limitAB, 2H, 5α CH₂), from 3.30 to 3.60 (mt, 6H, 2γ CH, 2δ CH₂O, 5γ CH and 5δCH₂O), 3.76 (mt, 1H, 2β CH), 3.90 (mt, 1H, 5β CH), 4.77 (d, J=5.5 Hz,1H, 2α CH), 8.43 (broad s, 1H, ═CH at 6), 8.61 (broad s, 1H, ═CH at 3).α_(D) ²⁰=−62.4

1.2 (c=0.5, water).

EXAMPLE 5

[0100] A solution of 5.0 g of L-gulose and 5.2 g of ammonium formate in20 cm³ of water is heated at reflux for 2 hours and then allowed to coolto room temperature. The mixture is concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 50

C. The black pasty residue is taken up in methanol, triturated andfiltered and the insoluble fraction is washed with methanol. Thefiltrate is concentrated under reduced pressure (2.7 kPa) at atemperature in the region of 50

C to give 7.5 g of a brown oil. The latter is purified by chromatographyon a silica (0.020-0.045 mm) column, elution being carried out with anethanol/n-butanol/aqueous ammonia solution/water 8/2/2/1 by volumemixture. The fractions containing the expected product are combined andconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 50

C, taken up successively in ethanol and ether and then reconcentrated.The oil obtained (0.6 g) is taken up in 5 cm³ of water and thenlyophilized. 0.47 g of1-[6-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol isthus obtained in the form of a brown lyophilisate. ¹H N.M.R. spectrum(400 MHz, d6-(CD₃)₂SO, at a temperature of 383 K, δ in ppm): 2.94 and3.03 (2 dd, respectively J=14 and 9 Hz and J=14 and 4 Hz, each 1H, 6αCH₂), from 3.40 to 3.70 (mt, 6H, 2γ CH, 2δ CH₂O, 6γ CH and 6δ CH₂O),3.88 (t, J=4 Hz, 1H, 2β CH), 4.01 (mt, 1H, 6β CH), 4.84 (d, J=4 Hz, 1H,2α CH), 8.42 (s, 1H, ═CH at 5), 8.57 (s, 1H, ═CH at 3). α_(D) ²⁰=−65.9

−1.4 (c=0.5, water).

EXAMPLE 6

[0101] A solution of 5.0 g of L-glucose and 8.8 g of ammonium formate in14 cm³ of water is heated at reflux for 3 hours and then allowed to coolto room temperature. The mixture is concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 65?C. The brown pastyresidue is taken up in methanol, triturated and filtered and theinsoluble fraction is washed with methanol. The filtrate is concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 50?C.This operation is repeated in ethanol to give a brown oil (6.2 g). Thelatter is purified by chromatography on a silica (0.020-0.045 mm)column, elution being carried out with an ethanol/n-butanol/aqueousammonia solution 8/2/1 by volume mixture. The fractions containing theexpected product are combined and concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 60?C. The oil obtained (0.5g) is taken up in 14 cm³ of ethanol, filtered while hot and thenrecrystallized. The crystals obtained are filtered, washed with ethanoland then pulled dry. After drying to constant weight at a temperature inthe region of 40?C, 0.35 g of1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol isobtained in the form of a beige crystalline solid melting at 114?C.(Rf=0.3; silica gel thin layer chromatography; eluentethanol/n-butanol/aqueous ammonia solution/water 8/2/2/1 by volumemixture)].

EXAMPLE 7

[0102] A solution of 2.0 g of D-psicose and 3.2 g of ammonium formate in3.4 cm³ of water is heated at reflux for 2 hours and then allowed tocool to room temperature. The mixture is diluted with 25 cm³ of ethylacetate and separated by settling. The aqueous phase is washed with 25cm³ of ethyl acetate and then concentrated under reduced pressure (2.7kPa) at a temperature in the region of 70?C. The brown oily residue istaken up in 100 cm³ of ethanol, triturated and filtered and theinsoluble fraction is washed with ethanol. The filtrate is concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 45?Cto give a brown paste (1.6 g). The latter is purified by chromatographyon a silica (0.020-0.045 mm) column, elution being carried out with anethanol/water 199/1 by volume mixture, then by chromatography on asilica (0.020-0.045 mm) column, elution being carried out with an ethylacetate/acetic acid/water 30/12/10 by volume mixture and finally bychromatography on a silica (0.020-0.045 mm) column at a pressure ofapproximately 1.5 ? 10⁵ Pa, elution being carried out with anethanol/n-butanol/aqueous ammonia solution 8/2/1 by volume mixture. Thefractions containing the expected product are combined and concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 50?C.The amber solid obtained (0.22 g) is taken up in a mixture of 5 cm³ ofethanol, and 0.25 cm³ of water, filtered while hot and thenrecrystallized. The crystals obtained are filtered, washed with ethanoland then pulled dry. After drying to constant weight, 65.5 mg of1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]-butane-1S,2S,3R,4-tetraolare obtained in the form of an ochre crystalline powder melting at141?C. ¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): 2.75 and3.08 (2 dd, respectively J=14 and 10 Hz and J=14 and 2.5 Hz, each 1H, 5αCH₂), from 3.30 to 3.50 (mt, 4H, 2γ CH, 5γ CH, 1H of the 2δ CH₂O and 1Hof the 5δ CH₂O), 3.60 (mt, 2H, the other H of the 2δ CH₂O and the otherH of the 5δ CH₂O), 3.79 (mt, 2H, 2β CH and 5β CH), 4.36 and 4.45 (2t,J=5.5 Hz, each 1H, OH at 2δ and OH at 5δ), 4.58, 4.64, 4.71 and 4.78 (4d, respectively J=4.5 Hz, J=6.5 Hz, J=5 Hz and J=5.5 Hz, 4H, OH), 4.82(t, J=5.5 Hz, 1H, 2α CH), 5.53 (d, J=5.5 Hz, 1H, OH at 2α), 8.41 (broads, 1H, ═CH at 6), 8.60 (broad s, 1H, ═CH at 3).

EXAMPLE 8

[0103] A solution of 5.0 g of D-galactose and 8.8 g of ammonium formatein 14 cm³ of water is heated at reflux for 45 minutes and then allowedto cool to room temperature. The mixture is diluted with 50 cm³ of ethylacetate and separated by settling. The aqueous phase is washed twicewith 50 cm³ of ethyl acetate and then concentrated under reducedpressure (2.7 kPa) at a temperature in the region of 65?C. The brownpasty residue is taken up in 100 cm³ of ethanol and triturated and thesupernatant is concentrated under reduced pressure (2.7 kPa) at atemperature in the region of 45?C (operation repeated once). Theresidual brown solid is taken up successively in methanol, ethanol andthen diethyl ether and evaporated to dryness under reduced pressure (2.7kPa) at a temperature in the region of 45?C. The residue is purified bychromatography on a silica (0.020-0.045 mm) column at a pressure ofapproximately 1.5 ? 10⁵ Pa and while eluting with anethanol/n-butanol/aqueous ammonia solution 8/2/1 by volume mixture. Thefractions containing the expected product are combined and concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 40?C.The yellow solid thus obtained (0.26 g) is taken up in a mixture of 3cm³ of ethanol and 0.25 cm³ of water, filtered while hot and thenrecrystallized. The solid obtained is filtered and then pulled dry.After drying under reduced pressure (2.7 kPa) at a temperature in theregion of 25?C, 119 mg of1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol areobtained in the form of an amber pasty solid which melts at 90-130?C(paste). ¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): 2.89(limit AB, 2H, 6α CH₂), from 3.30 to 3.55 (mt, 5H, 2δ CH₂O, 6δ CH₂O and6γ CH), from 3.70 to 3.85 (mt, 2H, 2γ CH and 2β CH), 3.92 (mt, 1H, 6βCH), 4.64 (d, J=8.5 Hz, 1H, 2α CH), 8.38 (s, 1H, ═CH at 5), 8.45 (s, 1H,═CH at 3).

[0104] The compounds of formula (I) exhibit advantageous pharmacologicalproperties. They are of hypoglycaemic type.

[0105] The hypoglycaemic activity of the compounds of formula (I) wasdetermined with respect to the hyperglycaemic response to the oraladministration of glucose in the normoglycaemic mouse, according to thefollowing protocol:

[0106] Swiss albino mice weighing between 22 and 26 g are left withoutnourishment for 2 hours. At the end of this period, the glycaemia ismeasured and, immediately after, a dose of glucose (2 g/kg) isadministered orally. Thirty minutes later, the glycaemia is once againmeasured. The mice which respond by a hyperglycaemia greater than 170mg/dl are selected and used to detect the hypoglycaemic activity of thecompounds according to the invention.

[0107] The mice thus chosen are divided into groups of at least 10animals. Several groups receive doses of 3 to 50 mg/kg of product in avehicle, such as water or a mixture of methylcellulose/tween and water,once daily by gastric intubation. The treatment lasts 4 days. On the 4thday, after the final treatment, the animals receive a dose of glucose (2g/kg) and the glycaemia is measured 20 to 40 minutes later. Thepercentage of inhibition of the hyperglycaemic response to theadministration of glucose is calculated with respect to the responsemeasured in the group treated with the vehicle.

[0108] In this test, the compounds according to the invention exhibit apercentage of inhibition of glycaemia of greater than or equal to 10%.

[0109] The compounds of general formula (I) according to the inventionexhibit a low toxicity. Their LD₅₀ is greater than 2000 mg/kg via theoral route in the mouse.

[0110] In human therapeutics, these products are useful in theprevention and treatment of diabetes and in particular type II diabetes(NID diabetes), obese diabetes, diabetes at the age of about fifty,metaplethoric diabetes, diabetes affecting the elderly and milddiabetes. They can be used as a supplement to insulin therapy ininsulin-dependent diabetes where they make it possible to graduallyreduce the dose of insulin, unstable diabetes, insulin-resistantdiabetes, and as a supplement to hypoglycaemic sulphamides when these donot provide a sufficient decrease in glycaemia. These products can alsobe used in complications of diabetes, such as hyperlipaemias, lipidmetabolism disorders, dyslipaemias and obesity. They are also useful inthe prevention and treatment of lesions of atherosclerosis and theircomplications (coronopathies, myocardial infarction, cardiomyopathies,progression of these three complications into left ventricularinsufficiency, various arteriopathies, arterites of the lower limbs withclaudication and progression into ulcers and gangrene, cerebral vascularinsufficiency and its complications and sexual impotence of vascularorigin), diabetic retinopathy and all its manifestations (increase incapillary permeability, capillary thrombosis and dilation,microaneurysms, arteriovenous shunt, venous dilation, punctiform andmacular haemorrhages, exudates, macular oedemas, manifestations ofproliferative retinopathy: neovessels, proliferative retinitis scars,haemorrhages of the vitreous body, retinal detachment), diabeticcataract, diabetic neuropathy in its various forms (peripheralpolyneuropathies and its manifestations such as paraesthesias,hyperaesthesias and pain, mononeuropathies, radiculopathies, autonomousneuropathies, diabetic amyotrophies), manifestations of diabetic foot(ulcers of the lower extremities and of the foot), diabetic nephropathyin its two diffuse and nodular forms, atheromatosis (rise in HDLlipoproteins promoting the elimination of cholesterol from the atheromaplaques, decrease in the LDL lipoproteins, decrease in the LDL/HDLratio, inhibition of oxidation of the LDLs, decrease in plaqueadhesiveness), hyperlipaemias and dyslipaemias (hypercholesterolaemias,hypertriglyceridaemias, normalization of the fatty acid level,normalization of uricaemia, normalization of the A and B apoproteins),cataracts, arterial hypertension and its consequences.

[0111] The medicaments according to the invention are composed of acompound according to the invention or a combination of these products,in the pure state or in the form of a composition in which it iscombined with any other pharmaceutically compatible product, which canbe inert or physiologically active. The medicaments according to theinvention can be employed orally, parenterally, rectally or topically.

[0112] As solid compositions for oral administration, there can be usedtablets, pills, powders (gelatin capsules, cachets) or granules. Inthese compositions, the active principle according to the invention ismixed with one or more inert diluents, such as starch, cellulose,sucrose, lactose or silica, under an argon stream. These composition canalso comprise substances other than the diluents, for example one ormore lubricants such as magnesium stearate or talc, a colorant, acoating (dragées) or a glaze.

[0113] As liquid compositions for oral administration, there can be usedpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents, such as water, ethanol, glycerol,vegetable oils or liquid paraffin. These compositions can comprisesubstances other than the diluents, for example wetting, sweetening,thickening, flavouring or stabilizing products.

[0114] The sterile compositions for parenteral administration canpreferably be solutions in aqueous or nonaqueous form, suspensions oremulsions. As solvent or vehicle, there can be employed water, propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil,injectable organic esters, for example ethyl oleate, or other suitableorganic solvents. These compositions can also contain adjuvants, inparticular wetting, isotonizing, emulsifying, dispersing and stabilizingagents. Sterilization can be performed in several ways, for example byaseptizing filtration, by incorporating sterilizing agents into thecomposition, by irradiation or by heating. They can also be prepared inthe form of sterile solid compositions which can be dissolved at thetime of use in sterile water or any other injectable sterile medium.

[0115] The compositions for rectal administration are suppositories orrectal capsules which contain, in addition to the active product,excipients such as cocoa butter, semisynthetic glycerides orpolyethylene glycols.

[0116] The compositions for topical administration can be, for example,creams, lotions, collyria, collutoria, nose drops or aerosols.

[0117] The doses depend on the desired effect, the duration of treatmentand the administration route used; they are generally between 150 mg and600 mg per day via the oral route for an adult with unit doses rangingfrom 50 mg to 200 mg of active substance.

[0118] In general, the doctor will determine the appropriate dosageaccording to the age, weight and all other factors specific to thesubject to be treated.

[0119] The following examples illustrate compositions according to theinvention:

EXAMPLE A

[0120] Hard gelatin capsules, with doses of 50 mg of active product,having the following composition are prepared according to the usualtechnique: Active product 50 mg Cellulose 18 mg Lactose 55 mg Colloidalsilica 1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesiumstearate 1 mg

EXAMPLE B

[0121] Tablets, with doses of 50 mg of active product, having thefollowing composition are prepared according to the usual technique:Active product 50 mg Lactose 104 mg Cellulose 40 mg Polyvidone 10 mgSodium carboxymethylstarch 22 mg Talc 10 mg Magnesium stearate 2 mgColloidal silica 2 mg Hydroxymethylcellulose, glycerol, titanium 245 mgoxide (72/3.5/24.5) mixture qs for 1 finished film-coated tabletcontaining

EXAMPLE C

[0122] An injectable solution containing 50 mg of active product havingthe following composition is prepared: Active product 50 mg Benzoic acid80 mg Benzyl alcohol 0.06 ml Sodium benzoate 80 mg Ethanol at 95% 0.4 mlSodium hydroxide 24 mg Propylene glycol 1.6 ml Water qs for 4 ml

[0123] The invention also relates to the use of the compounds of generalformula (I) in the preparation of pharmaceutical compositions of use inthe treatment or prevention of diabetes and complications of diabetes.

[0124]1. A pharmaceutical composition comprising at least one compoundof general formula:

[0125] in which

[0126] R₁ represents the stereoisomeric forms of the chain

—(CHOH)₃—CH₂OH   (II)

[0127] and

[0128] either (A) R₂ represents a hydrogen atom and R₃ represents thestereoisomeric forms of the chain

—CH₂—(CHOH)₂—CH₂OH   (III)

[0129] or (B) R2 represents the stereoisomeric forms of the chains

—(CHOH)₃—CH₂OH   (II)

[0130] or

—CH₂—(CHOH)₂—CH₂OH   (III)

[0131] and R₃ represents a hydrogen atom, or a salt thereof with anorganic or inorganic acid,

[0132] provided however, that said compound is not

[0133] fructosazine of formula

[0134] deoxyfructosazine of formula

[0135] or the compound of formula

[0136]2. A pharmaceutical composition according to claim 1 comprising acompound selected from the group consisting of:

[0137]1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0138]1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0139]1-[5-(1R,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0140]1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0141]1-[5-(1S,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0142]1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0143]1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0144]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0145]1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0146]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0147]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0148]1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0149]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0150]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0151]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol

[0152]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0153]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0154]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol

[0155]1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0156]1-[6-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0157] or a salt of such a compound with an inorganic or organic acid.

[0158]3. A compound of formula:

[0159] in which

[0160] R₁ represents the stereoisomeric forms of the chain

—(CHOH)₃—CH₂OH   (II)

[0161] and

[0162] either (A) R₂ represents a hydrogen atom and R₃ represents thestereoisomeric forms of the chain

—CH₂—(CHOH)₂—CH₂OH   (III)

[0163] or (B) R₂ represents the stereoisomeric forms of the chains

—(CHOH)₃—CH₂OH   (II)

[0164] or

—CH₂—(CHOH)₂—CH₂OH   (III)

[0165] and R₃ represents a hydrogen atom,

[0166] or a salt thereof with an inorganic or organic acid, provided,however, that said compound is not a compound having any of thefollowing structures:

[0167]4. A compound according to claim 3 selected from the groupconsisting of:

[0168]1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0169]1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0170]1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0171]1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol

[0172]1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0173]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0174]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0175]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0176]1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol

[0177]1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0178]1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0179] or a salt of such a compound with an inorganic or organic acid.

[0180]5. A compound according to claim 3 selected from the groupconsisting of:

[0181]1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol

[0182]1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol

[0183]1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol

[0184] and their salts with an inorganic or organic acid.

[0185]6. A process for the preparation of a compound according to claim3 in which R₁ of formula (I) represents the stereoisomeric forms of the—(CHOH)₃—CH₂OH chain (II), R₂ represents a hydrogen atom and R₃represents the stereoisomeric forms of the —CH₂—(CHOH)₂—CH₂OH chain(III), said process comprising reacting ammonium formate with an aldose,or a mixture of two aldoses, of the dextrorotatory or levorotatoryseries, of general formula:

CHO—CHOH—R₁   (X)

[0186] in which R₁ has the same meaning as in claim 3, isolating theproduct and optionally converting it to a salt.

[0187]7. A process according to claim 6 in which the aldose is selectedfrom D-gulose, D-galactose, D-allose, D-altrose, D-idose, D-talose,L-glucose, L-mannose, L-galactose, L-allose, L-altrose, L-idose,L-talose and L-gulose.

[0188]8. A process for the preparation of a compound according to claim3 in which R₁ of formula (I) represents the stereoisomeric forms of the—(CHOH)₃—CH₂OH chain (II), R₂ represents the stereoisomeric forms of the—(CHOH)₃—CH₂OH chains (II) and R₃ represents a hydrogen atom, saidprocess comprising treating aminoaldose, or a mixture of 2 aminoaldoses,of general formula CHO—CH(NH₂)—R₁ (XI) in which R₁ has the same meaningas in claim 3, isolating the product and optionally converting it to asalt with an inorganic or organic acid.

[0189]9. The process according to claim 8 in which said aminoaldose isD-galactosamine.

[0190]10. A process for the preparation of a compound according to claim3 in which R₁ of formula (I) represents the stereoisomeric forms of the—(CHOH)₃—CH₂OH chain (II), R₂ represents the stereoisomeric forms of the—CH₂—(CHOH)₂—CH₂OH chain (III) and R₃ represents a hydrogen atom, saidprocess comprising treating an aminoaldose, or a mixture of twoaminoaldoses of general formula CHO—CH(NH₂)—R₁ (XI), in which R₁ has thesame meaning as in claim 3, in acidic medium, isolating the product andoptionally converting it to a salt with an inorganic or organic acid.

[0191]11. A process according to claim 10 in which said aminoaldoses ormixture of aminoaldoses comprises D-galactosamine.

[0192]12. A process for the preparation of a compound according to claim3 in which R₁ of formula (I) is a stereoisomeric form of —(CHOH)₃—CH₂OHchain (II), R₂ is a stereoisomeric form of —CH₂—(CHOH)₂—CH₂OH chain(III) and R₃ is a hydrogen atom, said process comprising reacting aketose, or a mixture of two ketoses, of general formula HOCH₂—CO—R₁(XII) in which R₁ has the same meaning as in claim 3, with ammoniumformate and isolating the product and optionally converting the productto a salt with an inorganic or organic acid.

[0193]13. A process according to claim 12 wherein said ketose of formula(XII) is selected from D-psicose, D-sorbose, D-tagatose, L-psicose,L-fructose, L-sorbose and L-tagatose.

[0194]14. A method for the treatment or prevention of diabetes orcomplications of diabetes, this method comprising administering to apatient in need of such treatment an effective amount of a compound offormula (I)

[0195] in which

[0196] R₁ is any of the stereoisomeric forms of the chain

—(CHOH)₃—CH₂OH   (II)

[0197] and

[0198] either (A) R₂ is a hydrogen atom and R₃ is any of thestereoisomeric forms of the chain

—CH₂—(CHOH)₂—CH₂OH   (III)

[0199] or (B) R₂ is any of the stereoisomeric forms of the chains

—(CHOH)₃—CH₂OH   (II)

[0200] and

—CH₂—(CHOH)₂—CH₂OH   (III)

[0201] and R₃ is a hydrogen atom,

[0202] or their salts with an inorganic or organic acid, in apharmaceutically acceptable vehicle,

[0203] provided, however, that said compound is not

[0204] fructosazine of formula

[0205] or

[0206] deoxyfructosazine of formula

[0207] or

[0208] a compound of formula

EXAMPLE 6

[0209] A solution of 5.0 g of L-glucose and 8.8 9 of ammonium formate in14 cm³ of water is heated at reflux for 3 hours and then allowed to coolto room temperature. The mixture is concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 65 □C. The brown pastyresidue is taken up in methanol, triturated and filtered and theinsoluble fraction is washed with methanol. The filtrate is concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 50□C. This operation is repeated in ethanol to give a brown oil (6.2 g).The latter is purified by chromatography on a silica (0.020-0.045 mm)column, elution being carried out with an ethanol/n-butanol/aqueousammonia solution 8/2/1 by volume mixture. The fractions containing theexpected product are combined and concentrated under reduced pressure(2.7 kPa) at a temperature in the region of 60 □C. The oil obtained (0.5g) is taken up in 14 cm³ of ethanol, filtered while hot and thenrecrystallized. The crystals obtained are filtered, washed with ethanoland then pulled dry. After drying to constant weight at a temperature inthe region of 40 □C., 0.35 g of1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol isobtained in the form of a beige crystalline solid melting at 114 □C.(Rf=0.3; silica gel thin layer chromatography; eluentethanol/n-butanol/aqueous ammonia solution/water 8/2/2/1 by volumemixture)].

EXAMPLE 7

[0210] A solution of 2.0 g of D-psicose and 3.2 g of ammonium formate in3.4 cm³ of water is heated at reflux for 2 hours and then allowed tocool to room temperature. The mixture is diluted with 25 cm³ of ethylacetate and separated by settling. The aqueous phase is washed with 25cm³ of ethyl acetate and then concentrated under reduced pressure (2.7kPa) at a temperature in the region of 70° C. The brown oily residue istaken up in 100 cm³ of ethanol, triturated and filtered and theinsoluble fraction is washed with ethanol. The filtrate is concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 45□C. to give a brown paste (1.6 g). The latter is purified bychromatography on a silica (0.020-0.045 mm) column, elution beingcarried out with an ethanol/water 199/1 by volume mixture, then bychromatography on a silica (0.020-0.045 mm) column, elution beingcarried out with an ethyl acetate/acetic acid/water 30/12/10 by volumemixture and finalLy by chromatography on a silica (0.020-0.045 mm)column at a pressure of approximately 1.5□10⁵ Pa, elution being carriedout with an ethanol/n-butanol/aqueous ammonia solution 8/2/1 by volumemixture. The fractions containing the expected product are combined andconcentrated under reduced pressure (2.7 kPa) at a temperature in theregion of 50 □C. The amber solid obtained (0.22 g) is taken up in amixture of 5 cm³ of ethanol, and 0.25 cm³ of water, filtered while hotand then recrystallized. The crystals obtained are filtered, washed withethanol and then pulled dry. After drying to constant weight, 65.5 mg of1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]-butane-1S,2S,3R,4-tetraolare obtained in the form of an ochre crystalline powder melting at 141□C. ¹H N.M.R. spectrum (400 MHz, d6-(CD3) ₂SO, δ in ppm): 2.75 and 3.08(2 dd, respectively J=14 and 10 Hz and J=14 and 2.5 Hz, each 1H, 5aCH₂), from 3.30 to 3.50 (mt, 4H, 2γ CH, 5γ CH, 1H of the 26 CH₂O and 1Hof the 5δ CH₂O), 3.60 (mt, 2H, the other H of the 26 CH₂O and the otherH of the 5δ CH₂O), 3.79 (mt, 2H, 2β CH and 5β CH), 4.36 and 4.45 (2t,J=5.5 Hz, each 1H, OH at 2δ and OH at 5δ), 4.58, 4.64, 4.71 and 4.78 (4d, respectively J=4.5 Hz, J=6.5 Hz, J=5 Hz and J=5.5 Hz, 4H, OH), 4.82(t, J=5.5 Hz, 1H, 2α CH), 5.53 (d, J=5.5 Hz, 1H, OH at 2α), 8.41 (broads, 1H, ═CH at 6), 8.60 (broad s, 1H, ═CH at 3).

EXAMPLE 8

[0211] A solution of 5.0 g of D-galactose and 8.8 g of ammonium formatein 14 cm³ of water is heated at reflux for 45 minutes and then allowedto cool to room temperature. The mixture is diluted with 50 cm³ of ethylacetate and separated by settling. The aqueous phase is washed twicewith 50 cm³ of ethyl acetate and then concentrated under reducedpressure (2.7 kPa) at a temperature in the region of 65 □C. The brownpasty residue is taken up in 100 cm³ of ethanol and triturated and thesupernatant is concentrated under reduced pressure (2.7 kPa) at atemperature in the region of 45 □C. operation repeated once). Theresidual brown solid is taken up successively in methanol, ethanol andthen diethyl ether and evaporated to dryness under reduced pressure (2.7kPa) at a temperature in the region of 45 □C. The residue is purified bychromatography on a silica (0.020-0.045 mm) column at a pressure ofapproximately 1.5□10⁵ Pa and while eluting with anethanol/n-butanol/aqueous ammonia solution 8/2/1 by volume mixture. Thefractions containing the expected product are combined and concentratedunder reduced pressure (2.7 kPa) at a temperature in the region of 40□C. The yellow solid thus obtained (0.26 g) is taken up in a mixture of3 cm³ of ethanol and 0.25 cm³ of water, filtered while hot and thenrecrystallized. The solid obtained is filtered and then pulled dry.After drying under reduced pressure (2.7 kPa) at a temperature in theregion of 25 □C., 119 mg of1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol areobtained in the form of an amber pasty solid which melts at 90-130 □C.(paste). ¹H N.M.R. spectrum (400 MHz, d6-(CD₃)₂SO, δ in ppm): 2.89(limit AB, 2H, 6α CH₂), from 3.30 to 3.55 (mt, 5H, 2δ CH₂O, 6δ CH₂O and6γ CH), from 3.70 to 3.85 (mt, 2H, 2γ CH and 2β CH), 3.92 (mt, 1H, 6βCH), 4.64 (d, J=8.5 Hz, 1H, 2α CH), 8.38 (s, 1H, ═CH at 5), 8.45 (s, 1H,═CH at 3).

[0212] The compounds of formula (I) exhibit advantageous pharmacologicalproperties. They are of hypoglycaemic type.

[0213] The hypoglycaemic activity of the compounds of formula (I) wasdetermined with respect to the hyperglycaemic response to the oraladministration of glucose in the normoglycaemic mouse, according to thefollowing protocol:

[0214] Swiss albino mice weighing between 22 and 26 g are left withoutnourishment for 2 hours. At the end of this period, the glycaemia ismeasured and, immediately after, a dose of glucose (2 g/kg) isadministered orally. Thirty minutes later, the glycaemia is once againmeasured. The mice which respond by a hyperglycaemia greater than 170mg/dl are selected and used to detect the hypoglycaemic activity of thecompounds according to the invention.

[0215] The mice thus chosen are divided into groups of at least 10animals. Several groups receive doses of 3 to 50 mg/kg of product in avehicle, such as water or a mixture of methylcellulose/tween and water,once daily by gastric intubation. The treatment lasts 4 days. On the 4thday, after the final treatment, the animals receive a dose of glucose (2g/kg) and the glycaemia is measured 20 to 40 minutes later. Thepercentage of inhibition of the hyperglycaemic response to theadministration of glucose is calculated with respect to the responsemeasured in the group treated with the vehicle.

[0216] In this test, the compounds according to the invention exhibit apercentage of inhibition of glycaemia of greater than or equal to 10%.

[0217] The compounds of general formula (I) according to the inventionexhibit a low toxicity. Their LD₅₀ is greater than 2000 mg/kg via theoral route in the mouse.

[0218] In human therapeutics, these products are useful in theprevention and treatment of diabetes and in particular type II diabetes(NID diabetes), obese diabetes, diabetes at the age of about fifty,metaplethoric diabetes, diabetes affecting the elderly and milddiabetes. They can be used as a supplement to insulin therapy ininsulin-dependent diabetes where they make it possible to graduallyreduce the dose of insulin, unstable diabetes, insulin-resistantdiabetes, and as a supplement to hypoglycaemic sulphamides when these donot provide a sufficient decrease in glycaemia. These products can alsobe used in complications of diabetes, such as hyperlipaemias, lipidmetabolism disorders, dyslipaemias and obesity. They are also useful inthe prevention and treatment of lesions of atherosclerosis and theircomplications (coronopathies, myocardial infarction, cardiomyopathies,progression of these three complications into left ventricularinsufficiency, various arteriopathies, arterites of the lower limbs withclaudication and progression into ulcers and gangrene, cerebral vascularinsufficiency and its complications and sexual impotence of vascularorigin), diabetic retinopathy and all its manifestations (increase incapillary permeability, capillary thrombosis and dilation,microaneurysms, arteriovenous shunt, venous dilation, puncti.form andmacular haemorrhages, exudates, macular oedemas, manifestations ofproliferative retinopathy: neovessels, proliferative retinitis scars,haemorrhages of the vitreous body, retinal detachment), diabeticcataract, diabetic neuropathy in its various forms (peripheralpolyneuropathies and its manifestations such as paraesthesias,hyperaesthesias and pain, mononeuropathies, radiculopathies, autonomousneuropathies, diabetic amyotrophies), manifestations of diabetic foot(ulcers of the lower extremities and of the foot), diabetic nephropathyin its two diffuse and nodular forms, atheromatosis (rise in HDLlipoproteins promoting the elimination of cholesterol from the atheromaplaques, decrease in the LDL lipoproteins, decrease in the LDL/HDLratio, inhibition of oxidation of the LDLs, decrease in plaqueadhesiveness), hyperlipaemias and dyslipaemias (hypercholesterolaemias,hypertriglyceridaemias, normalization of the fatty acid level,normalization of uricaemia, normalization of the A and B apoproteins),cataracts, arterial hypertension and its consequences.

[0219] The medicaments according to the invention are composed of acompound according to the invention or a combination of these products,in the pure state or in the form of a composition in which it iscombined with any other pharmaceutically compatible product, which canbe inert or physiologically active. The medicaments according to theinvention can be employed orally, parenterally, rectally or topically.

[0220] As solid compositions for oral administration, there can be usedtablets, pills, powders (gelatin capsules, cachets) or granules. Inthese compositions, the active principle according to the invention ismixed with one or more inert diluents, such as starch, cellulose,sucrose, lactose or silica, under an argon stream. These composition canalso comprise substances other than the diluents, for example one ormore lubricants such as magnesium stearate or talc, a colorant, acoating (dragées) or a glaze.

[0221] As liquid compositions for oral administration, there can be usedpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents, such as water, ethanol, glycerol,vegetable oils or liquid paraffin. These compositions can comprisesubstances other than the diluents, for example wetting, sweetening,thickening, flavouring or stabilizing products.

[0222] The sterile compositions for parenteral administration canpreferably be solutions in aqueous or nonaqueous form, suspensions oremulsions. As solvent or vehicle, there can be employed water, propyleneglycol, a polyethylene glycol, vegetable oils, in particular olive oil,injectable organic esters, for example ethyl oleate, or other suitableorganic solvents. These compositions can also contain adjuvants, inparticular wetting, isotonizing, emulsifying, dispersing and stabilizingagents. Sterilization can be performed in several ways, for example byaseptizing filtration, by incorporating sterilizing agents into thecomposition, by irradiation or by heating. They can also be prepared inthe form of sterile solid compositions which can be dissolved at thetime of use in sterile water or any other injectable sterile medium.

[0223] The compositions for rectal administration are suppositories orrectal capsules which contain, in addition to the active product,excipients such as cocoa butter, semisynthetic glycerides orpolyethylene glycols.

[0224] The compositions for topical administration can be, for example,creams, lotions, collyria, collutoria, nose drops or aerosols.

[0225] The doses depend on the desired effect, the duration of treatmentand the administration route used; they are generally between 150 mg and600 mg per day via the oral route for an adult with unit doses rangingfrom 50 mg to 200 mg of active substance.

[0226] In general, the doctor will determine the appropriate dosageaccording to the age, weight and all other factors specific to thesubject to be treated.

[0227] The following examples illustrate compositions according to theinvention:

EXAMPLE A

[0228] Hard gelatin capsules, with does of 50 mg of active product,having the following composition are prepared according to the usualtechnique: Active product 50 mg Cellulose 18 mg Lactose 55 mg Colloidalsilica 1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesiumstearate 1 mg

EXAMPLE B

[0229] Tablets, with doses of 50 mg of active product, having thefollowing composition are prepared according to the usual technique:Active product 50 mg Lactose 104 mg Cellulose 40 mg Polyvidone 10 mgSodium carboxymethylstarch 22 mg Talc 10 mg Magnesium stearate 2 mgColloidal silica 2 mg Hydroxymethylcellulose, glycerol, titan- 245 mgium oxide (72/3.5/24.5) mixture qs for 1 finished film-coated tabletcontaining

EXAMPLE C

[0230] An injectable solution containing 50 mg of active product havingthe following composition is prepared: Active product 50 mg Benzoic acid80 mg Benzyl alcohol 0.06 ml Sodium benzoate 80 mg Ethanol at 95% 0.4 mlSodium hydroxide 24 mg Propylene glycol 1.6 ml Water qs for 4 ml

[0231] The invention also relates to the use of the compounds of generalformula (I) in the preparation of pharmaceutical compositions of use inthe treatment or prevention of diabetes and complications of diabetes.

1. A pharmaceutical composition comprising at least one compound ofgeneral formula:

in which R₁ represents the stereoisomeric forms of the chain—(CHOH)₃—CH₂OH   (II) and either (A) R₂ represents a hydrogen atom andR₃ represents the stereoisomeric forms of the chain —CH₂—(CHOH)₂—CH₂OH  (III) or (B) R₂ represents the stereoisomeric forms ofthe chains —(CHOH)₃—CH₂OH   (II) or —CH₂—(CHOH)₂—CH₂OH  (III) and R₃represents a hydrogen atom, or a salt thereof with an organic orinorganic acid, provided however, that said compound is not fructosazineof formula

deoxyfructosazine of formula

or the compound of formula


2. A pharmaceutical composition according to claim 1 comprising acompound selected from the group consisting of:1-[5-(1R,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol1-[5-(1R,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[5-(1S,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3R,4-tetraol1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3S,4-tetraol1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol1-[6-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol ora salt of such a compound with an inorganic or organic acid.
 3. Acompound of formula:

in which R₁ represents the stereoisomeric forms of the chain—(CHOH)₃—CH₂OH  (II) and either (A) R₂ represents a hydrogen atom and R₃represents the stereoisomeric forms of the chain—CH₂—(CHOH)₂—CH₂OH  (III) or (B) R₂ represents the stereoisomeric formsof the chains —(CHOH)₃—CH₂OH   (II) or —CH₂—(CHOH)₂—CH₂OH  (III) and R₃represents a hydrogen atom, or a salt thereof with an inorganic ororganic acid, provided, however, that said compound is not a compoundhaving any of the following structures:


4. A compound according to claim 3 selected from the group consistingof:1-[5-(1R,2R,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol1-[5-(1S,2R,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[5-(1S,2S,3R,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol1-[5-(1S,2S,3S,4-tetrahydroxybutyl)pyrazin-2-yl]butane-1S,2S,3S,4-tetraol1-[5-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol1-[6-(2R,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2R,3S,4-tetraol1-[6-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[6-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol ora salt of such a compound with an inorganic or organic acid.
 5. Acompound according to claim 3 selected from the group consisting of:1-[5-(2S,3S,4-trihydroxybutyl)pyrazin-2-yl]butane-1R,2S,3S,4-tetraol1-[5-(2R,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2R,3R,4-tetraol1-[5-(2S,3R,4-trihydroxybutyl)pyrazin-2-yl]butane-1S,2S,3R,4-tetraol andtheir salts with an inorganic or organic acid.
 6. A process for thepreparation of a compound according to claim 3 in which R, of formula(I) represents the stereoisomeric forms of the —(CHOH)₃—CH₂OH chain(II), R₂ represents a hydrogen atom and R₃ represents the stereoisomericforms of the —CH₂—(CHOH)₂—CH₂OH chain (III), said process comprisingreacting ammonium formate with an aldose, or a mixture of two aldoses,of the dextrorotatory or levorotatory series, of general formula:CHO—CHOH—R₁  (X) in which R₁ has the same meaning as in claim 3,isolating the product and optionally converting it to a salt.
 7. Aprocess according to claim 6 in which the aldose is selected fromD-gulose, D-galactose, D-allose, D-altrose, D-idose, D-talose,L-glucose, L-mannose, L-galactose, L-allose, L-altrose, L-idose,L-talose and L-gulose.
 8. A process for the preparation of a compoundaccording to claim 3 in which R₁ of formula (I) represents thestereoisomeric forms of the —(CHOH)₃—CH₂OH chain (II), R₂ represents thestereoisomeric forms of the —(CHOH)₃—CH₂OH chains (II) and R₃ representsa hydrogen atom, said process comprising treating aminoaldose, or amixture of 2 aminoaldoses, of general formula CHO—CH(NH₂)—R₁ (XI) inwhich R₁ has the same meaning as in claim 3, isolating the product andoptionally converting it to a salt with an inorganic or organic acid. 9.The process according to claim 8 in which said aminoaldose isD-galactosamine.
 10. A process for the preparation of a compoundaccording to claim 3 in which R₁ of formula (I) represents thestereoisomeric forms of the —(CHOH)₃—CH₂OH chain (II), R₂ represents thestereoisomeric forms of the —CH₂—(CHOH)₂—CH₂OH chain (III) and R₃represents a hydrogen atom, said process comprising treating anaminoaldose, or a mixture of two aminoaldoses of general formulaCHO—CH(NH₂)—R₁ (XI), in which R₁ has the same meaning as in claim 3, inacidic medium, isolating the product and optionally converting it to asalt with an inorganic or organic acid.
 11. A process according to claim10 in which said aminoaldoses or mixture of aminoaldoses comprisesD-galactosamine.
 12. A process for the preparation of a compoundaccording to claim 3 in which R₁ of formula (I) is a stereoisomeric formof —(CHOH)₃—CH₂OH chain (II), R₂ is a stereoisomeric form of—CH₂—(CHOH)₂—CH₂OH chain (III) and R₃ is a hydrogen atom, said processcomprising reacting a ketose, or a mixture of two ketoses, of generalformula HOCH₂—CO—R₁ (XII) in which R₁ has the same meaning as in claim3, with ammonium formate and isolating the product and optionallyconverting the product to a salt with an inorganic or organic acid. 13.A process according to claim 12 wherein said ketose of formula (XII) isselected from D-psicose, D-sorbose, D-tagatose, L-psicose, L-fructose,L-sorbose and L-tagatose.
 14. A method for the treatment or preventionof diabetes or complications of diabetes, this method comprisingadministering to a patient in need of such treatment an effective amountof a compound of formula (I)

in which R₁ is any of the stereoisomeric forms of the chain—(CHOH)₃—CH₂OH   (II) and either (A) R₂ is a hydrogen atom and R₃ is anyof the stereoisomeric forms of the chain —CH₂—(CHOH)₂—CH₂OH  (III) or(B) R₂ is any of the stereoisomeric forms of the chains—(CHOH)₃—CH₂OH  (II) and —CH₂—(CHOH)₂—CH₂OH  (III) and R₃ is a hydrogenatom, or their salts with an inorganic or organic acid, in apharmaceutically acceptable vehicle, provided, however, that saidcompound is not fructosazine of formula

deoxyfructosazine of formula

a compound of formula